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Current diagnosis and treatment of rheumatoid arthritis (RA) is still challenging. More than one-third of patients with RA could not be accurately diagnosed because of lacking biomarkers. Our recent study reported that scavenger receptor-A (SR-A) is a biomarker for RA, especially for anticyclic citrullinated peptide antibody (anti-CCP)-negative RA. Here, we further identified the B cell autoantigenic epitopes of SR-A. By a large-scale multicenter study including one training and three validation cohorts of 1954 participants, we showed that anticitrullinated SR-A peptide antibody (anti-CSP) was exclusively elevated in RA as a biomarker, particularly useful for seronegative RA. Combination of anti-CSP with anti-CCP demonstrated superior diagnostic value for RA, with sensitivity of 84.83% and specificity of 92.43%. Moreover, RA anti-CSP revealed distinct glycosylation patterns, capable of provoking inflammation in cartilage organoids and exacerbating disease progression in experimental arthritis. Together, these data identify anti-CSP as an RA autoantibody clinically applicable and actively involved in disease pathogenesis.

Objectives: Viruses have been considered as important participants in the development of rheumatoid arthritis (RA). However, the profile of enteric virome and its role in RA remains elusive. This study aimed to investigate the atlas and involvement of virome in RA pathogenesis., Methods: Faecal samples from 30 pairs of RA and healthy siblings that minimise genetic interferences were collected for metagenomic sequencing. The α and β diversity of the virome and the virome-bacteriome interaction were analysed. The differential bacteriophages were identified, and their correlations with clinical and immunological features of RA were analysed. The potential involvement of these differential bacteriophages in RA pathogenesis was further investigated by auxiliary metabolic gene annotation and molecular mimicry study. The responses of CD4 + T cells and B cells to the mimotopes derived from the differential bacteriophages were systemically studied., Results: The composition of the enteric bacteriophageome was distorted in RA. The differentially presented bacteriophages correlated with the immunological features of RA, including anti-CCP autoantibody and HLA-DR shared epitope. Intriguingly, the glycerolipid and purine metabolic genes were highly active in the bacteriophages from RA. Moreover, peptides of RA-enriched phages, in particular Prevotella phage and Oscillibacter phage could provoke the autoimmune responses in CD4 + T cells and plasma cells via molecular mimicry of the disease-associated autoantigen epitopes, especially those of Bip., Conclusions: This study provides new insights into enteric bacteriophageome in RA development. In particular, the aberrant bacteriophages demonstrated autoimmunity-provoking potential that would promote the occurrence of the disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: The routine biomarkers for rheumatoid arthritis (RA), including anticyclic citrullinated peptide antibody (anti-CCP), rheumatoid factor (RF), immunoglobulin M (IgM), erythrocyte sedimentation rate (ESR), and C-reaction protein (CRP) have limited sensitivity and specificity. Scavenger receptor-A (SR-A) is a novel RA biomarker identified by our group recently, especially for seronegative RA. Here, we performed a large-scale multicentre study to further assess the diagnostic value of SR-A in combination with other biomarkers for RA., Methods: The performance of SR-A in combination with other biomarkers for RA diagnosis was first revealed by a pilot study, and was further elucidated by a large-scale multicentre study. A total of 1129 individuals from 3 cohorts were recruited in the study, including RA patients, healthy controls, and patients with other common rheumatic diseases. Diagnostic properties were evaluated by the covariate-adjusted receiver-operating characteristic (AROC) curve, sensitivity, specificity and clinical association, respectively., Results: Large-scale multicentre analysis showed that SR-A and anti-CCP dual combination was the optimal method for RA diagnosis, increasing the sensitivity of anti-CCP by 13% (87% vs 74%) while maintaining a specificity of 90%. In early RA patients, SR-A and anti-CCP dual combination also showed promising diagnostic value, increasing the sensitivity of anti-CCP by 7% (79% vs 72%) while maintaining a specificity of 94%. Moreover, SR-A and anti-CCP dual combination was correlated with ESR, IgM, and autoantibodies of RA patients, further revealing its clinical significance., Conclusion: SR-A and anti-CCP dual combination could potentially improve early diagnosis of RA, thus improving the prognosis and reducing mortality., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: B10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases., Methods: The frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α -/- and B cell-specific SHIP-1 -/- mouse disease model studies., Results: TNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α -/- mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells., Conclusions: TNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Pain-depression comorbidity has become a great burden to individuals and society. Nevertheless, the mechanisms underlying comorbid diseases have still not been fully revealed. Ultrasound-guided pulsed radiofrequency (PRF) on peripheral nerves, which produces remarkable analgesia via high-frequency electromagnetic energy, has become a main, minimally invasive treatment for chronic neuropathic pain., Objectives: The aim of this study was to explore the effect of ultrasound-guided PRF on the sciatic nerve of spared nerve injury (SNI) rats to relieve pain-induced depression., Study Design: Experimental trial in rats., Setting: The research took place in the Laboratory of The First Affiliated Hospital of Wenzhou Medical University., Methods: Sixty male Wistar rats were randomly divided into a sham group, an SNI group, an SNI + free-PRF group, and an SNI + PRF group. Ultrasound-guided PRF was applied to the sciatic nerve on day 7 after SNI. The basal paw mechanical withdrawal threshold (PMWT) was evaluated as a measure for pain-related behavior, and a  sucrose preference test was performed as a measure for depression-related behavior. The expression levels of spinal interferon regulatory factor 8 (IRF8) and of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) were also studied on days 21 and 42., Results: The results showed that the PMWT was significantly decreased in rats following SNI operation; the decreased levels of PMWT were reversed in the SNI + PRF group after the application of PRF on the sciatic nerve on day 7. There were no statistically significant differences among the groups in the sucrose preference rate on day 21 after SNI operation. The sucrose preference rate on day 42 was higher in the SNI + PRF group than in the SNI + free-PRF group. Western blot and reverse transcription polymerase chain reaction also demonstrated that ultrasound-guided PRF on the sciatic nerve downregulated overexpression of spinal IRF8 and increased the levels of BDNF in the PFC., Limitations: This study was performed using only an SNI rat model which cannot represent all rodent neuropathic pain models. Only the short-term effectiveness of ultrasound-guided PRF on the sciatic nerve of SNI rats was investigated. The BDNF changes of other important brain areas were not taken into consideration in this study., Conclusions: These findings suggest that ultrasound-guided PRF on sciatic nerve could alleviate pain-induced depression. The mechanisms of this treatment may be involved in the downregulated spinal IRF8 and the increased BDNF in PFC.